Chronic stress has been shown to be associated clinically with formation of depression in patients and hormones are known to mediate certain clinical manifestations of mood disorders. Chronic restraint stress induces a morphological reorganization of neurons in certain areas of rodent brain, effects that are also accompanied by behavioral changes. Although the precise mechanisms underlying these effects remain to be elucidated, a growing body of data suggests that alterations in neuroprotection and mitochondrial functions of glucocorticoid receptors may play an important role in regulating various forms of synaptic and neuronal plasticity;we have sought to investigate the mitochondrial functions regulated by steroid hormones during chronic stress. Glucocorticoids play an important biphasic role in modulating synaptic and neural events, with low doses enhancing synaptic and neuronal plasticity and chronic, higher doses producing inhibition. We undertook a series of experiments to elucidate the mechanisms underlying these biphasic effects. We found that 1) glucocorticoid receptors (GRs) formed a complex with the anti-apoptotic protein Bcl-2 in response to corticosterone treatment, and 2) translocated with Bcl-2 into mitochondria after acute treatment with low or high doses of corticosterone in primary cortical neurons. However, after three days of treatment, high but not low doses of corticosterone resulted in a decrease in GR and Bcl-2 levels in mitochondria. In addition, three independent measures of mitochondrial function, mitochondrial calcium holding capacity, mitochondrial oxidation, and membrane potential were also regulated by long-term corticosterone treatment in an inverted U-shape. This regulation of mitochondrial function by corticosterone correlated with neuroprotection: that is, treatment with low doses of corticosterone demonstrated a neuroprotective effect, whereas treatment with high doses enhanced kainic acid (KA, a neural toxin)-induced toxicity of cortical neurons. As with the in vitro studies, Bcl-2 levels in the mitochondria of the prefrontal cortex were significantly decreased, along with GR levels, after long-term treatment with high-dose corticosterone. These findings have the potential to contribute to a more complete understanding of the mechanisms by which glucocorticoids and chronic stress regulate cellular plasticity and resilience, and to inform the future development of improved therapeutic treatments. Recent studies focused on the molecular mechanism of the GR/Bcl-2 trafficking. Bcl-2 associated athanogene (BAG-1), a common target of lithium and valproate, interacts with glucocorticoid receptors (GRs), Bcl-2 (which is associated with risk of bipolar disorder), heat shock protein (HSP) 70, and inhibits GR receptor nucleus translocation in response to corticosterone (CORT). In addition, BAG-1 transgenic mice showed less anxious-like behavior on the elevated plus maze test and more resilience in recovering from learned helplessness behavior and amphetamine-induced manic-like behaviors. Preliminary data from the collaboration with Dr. McEwens laboratories showed that Bag-1 expression was reduced after chronic stress in the hippocampal CA3 region, a brain area that is sensitive to seizure-induced excitotoxicity and also one that shows dendritic remodeling in response to chronic stress in both rats and mice. We recently found that GR/Bcl-2/Bag-1 complex formation is enhanced after CORT treatment. Further investigation will address whether or not overexpression of Bag-1 will protect CORT induced mitochondrial damage during chronic stress. The outcome of our work is expected to have a high impact because the identified mechanisms of regulation of mitochondrial functions during chronic stress are anticipated to provide new target and new potential drugs for preventive or therapeutic intervention, which will help millions of people in America. Furthermore, this research also has the potential to contribute to a more complete understanding of the mechanisms by which chronic stress and hormones regulate cellular plasticity and resilience. This cellular plasticity and resilience are essential protective factors for the development of stress-induced psychiatric disorders, such as depression, and PTSD.